JP2006522133A - Non-aqueous single phase media and formulations utilizing such media - Google Patents

Abstract

[Solution]
The present invention comprises materials and methods for providing a vehicle that is useful for providing drug formulations that address the potential shortcomings of known non-aqueous formulations. In particular, the present invention includes non-aqueous media formed using a combination of a polymer and a solvent that yields a media that is miscible in water. Non-aqueous media facilitates the formation of drug formulations that are stable over time, even when stored at or exposed to elevated temperatures. Furthermore, the miscible medium according to the present invention does not form a high viscosity polymer phase when mixed with water, so that part of the distribution conduit contained in the dispensing device used to administer the drug formulation or Allows the preparation of drug formulations that work to reduce the occurrence of complete occlusion.

Description

  This application is a US Provisional Patent Application Serial No. 60/459, filed Mar. 31, 2003, for “Non-Aqueous Single Phase Media and Formulations Utilizing Such Media”. , Request the advantage of the filing date of No. 300.

  The present invention relates to a single phase medium useful in preparing a drug formulation. In particular, the present invention is non-aqueous, biocompatible, can provide a stable suspension of particulate drug material, and facilitates the dispensing of drug material at a controlled rate over an extended period of time. Relates to a single phase medium.

  Implanted devices are known in the art that can dispense a desired dose of an advantageous drug over an extended period of time. For example, U.S. Pat. Nos. 5,034,229, 5,557,318, 5,110,596, 5,728,396, 5,985,305, 6,113,938, 6,156,331, 6,375 , 978, and 6,395,292 are active agents, such as solutions or suspensions, at a desired rate over a long period of time (ie, a period ranging from longer than one week to more than one year). Teaches an osmotically driven device that can distribute formulation. Another example implanter includes a regulated implant pump that provides a steady, adjustable or programmable flow of advantageous drug formulation, which is available from Raynham, Massachusetts, et al. Commercially available from Codman, Medtronic, Minneapolis, Minneapolis, Tricumud, Germany, and Medizen Technique GmbH. Further examples of implantation devices are described in US Pat. Nos. 6,283,949, 5,976,109,5,836,935, 5,511,355. Because these devices can be designed to dispense the desired active agent at therapeutic levels over a long period of time, implantable dispensing systems allow frequent visits to health care providers and repeated self-treatments. Without requiring, long-term therapeutic administration of the desired active agent can be advantageously provided. Therefore, the implantable dispensing device can increase patient compliance, reduce inflammation at the site of administration, reduce occupational risks for health care providers, reduce the risk of waste, and increase dose control. Can act to provide increased treatment efficiency.

However, it has proven difficult to dispense beneficial drugs, including biomolecular materials, over a long period of time using an implantable drug delivery system. The term “biomolecular material”, when used, is a peptide, polypeptide, protein, nucleic acid, virus, antibody, and any other naturally derived, synthesized or recombinant, including nucleic acids or amino acids. It refers to beneficial chemicals that have been manufactured. The term “biomolecular material” includes lipoproteins and post-transcriptional variants, such as glycosylated proteins. The term has proteins and / or D amino acids, modified and induced or non-naturally occurring D- or L-form amino acids, and / or peptone units as part of their structure, Contains protein and / or protein material. Among other challenges, two problems must be addressed when attempting to dispense biomolecular material over time from an implanted dispensing device. First, the biomolecular material must be included in a formulation that substantially maintains the stability of the material at elevated temperatures (ie, 37 ° C. and above) over the working life of the device. Secondly, the biomolecular material must be formulated in a manner that allows for the distribution of the biomolecular material from the implantable device in the desired environment of operation for an extended period of time. This second challenge is particularly difficult when the biomolecular material is contained in a flowable composition that is dispensed from the device over a long period of time at a low flow rate (ie, < 100 μl / day). There was found.

  Biomolecular materials can degrade through one or more of several different mechanisms, including deamidation, oxidation, hydrolysis, disulfide exchange, and racemization. Significantly, water is a reactant in many of the associated degradation pathways. Moreover, water functions as a plasticizer, facilitating diffusion and irreversible aggregation of biomolecular materials. In order to work with stability issues formed by aqueous formulation of biomolecular material, dry powder formulation of biomolecular material is known particles, for example, by known lyophilization, spray drying or dehydration techniques. Formed using a forming process. Although dry powder formulations of biomolecular materials have been shown to provide adequate stability characteristics, they are not only stable over long periods of time, but are also flowable and easily from an implantable dispensing device It is desirable to provide a formulation that can be distributed.

  In order to provide a non-aqueous drug formulation that contains biomolecular material and can be dispensed from an implantable device, so that the biomolecular material is stable over time at elevated temperatures, ALZA The formulation and method described in International Publication No. WO 00/45790 (published '790) was developed. The '790 published patent describes a non-aqueous media formulation formulated using at least two of polymers, solvents and surfactants. The '790 published media formulation is suitable for preparing drug suspensions that contain biomolecular drug materials and are stable over time even at elevated temperatures. However, under some circumstances, the formulation taught in the '790 published patent may prohibit drug delivery to the desired work environment. In particular, when the formulation taught in the '790 published patent is exposed to an aqueous liquid, such as a physiological fluid, within the distribution conduit of the device used to distribute the formulation, the polymer contained in the medium , Tends to phase separate from solvent to aqueous liquid. When the polymer is separated in the aqueous liquid, the concentration of the polymer in the aqueous liquid increases to such an extent that a very viscous polymer gel or precipitate is formed in the distribution conduit, so that the distribution conduit This may result in partial or complete occlusion and interfere with the desired operation of the dispensing device. The possibility of such an occlusion situation occurs when the shape of the conduit forms such that the aqueous liquid interferes with drug formulation in a limited area over a relatively long period of time (eg, hours or days). If it has been increased.

  Forming a drug formulation that not only facilitates the distribution of biomolecular material from the implant device, but also shows that the formulation reduces the likelihood of shielding or occluding the distribution conduit of the device being dispensed. Providing a enabling medium would be an improvement in the art. Ideally, such a formulation would allow the biomolecular material to be dispensed from the implant device at various controlled rates and was contained internally for extended periods even at elevated temperatures. Works to maintain the stability of biomolecular materials.

  In one aspect, the present invention comprises materials and methods for providing a vehicle that is useful for providing drug formulations that address the potential shortcomings of known non-aqueous formulations. In particular, the present invention includes non-aqueous media formed using a combination of a polymer and a solvent that yields a media that is miscible in water. The term “miscible in water” as used herein results in a phase separation of the polymer from the solvent such that a high viscosity polymer phase is formed at a temperature range representative of the selected working environment. Refers to a medium that can be mixed with water in all proportions. For purposes of the present invention, “high viscosity polymer phase” refers to a polymer-containing component that exhibits a viscosity greater than that of the medium before the medium is mixed with water. The medium according to the present invention does not form a high viscosity polymer phase when mixed with water, thus preventing the occurrence of partial or complete blockage of the distribution conduit contained in the distribution device used to administer the formulation. Allows the formation of drug formulations that act to reduce.

  Although various polymer and solvent combinations can be used to form the media according to the present invention, the polymer and solvent are not only miscible with water, but the suspension is exposed to elevated temperatures. Sometimes, they are selected and combined in a manner that provides a suitable medium for forming a suspension of drug material that operates to maintain drug stability. The terms “stable” and “stability”, as used herein, refer to both chemical and physical stability of a drug material. In particular, after maintaining the formulation at 37 ° C. for 2 months, the formulation is only about 35% or less of the drug substance by chemical route, such as by oxidation, deamidation and hydrolysis. If not degraded, it is considered chemically stable according to the present invention. A formulation is also considered physically stable if only about 15% or less of the drug substance contained in the formulation is degraded by aggregation under the same conditions. Drug formulation is stable according to the present invention when at least 65% of the drug substance is physically and chemically stable after 2 months at 37 ° C.

  In another aspect, the present invention relates to a drug formulation comprising a drug dispersed in a medium according to the present invention. The drug included in the drug formulation according to the present invention is preferably provided as a particulate material. The particulate material may be a substantially pure drug material or may be formed from drug particles comprising drug material plus one or more coatings, preservatives, excipients or adjuvants. . The medium according to the present invention is particularly suitable for providing a drug formulation incorporating a particulate biomolecular material, but the formulation of the present invention is not limited to that example. The term “medicament” as used herein refers to any composition or material that provides a therapeutic or beneficial effect and includes, for example, pharmaceuticals, vitamins, nutrients, or food supplements. ing. However, in each of the drug formulation embodiments of the present invention, the media is selected and a particulate drug material is prepared so that the drug does not dissolve in one or more of the media components.

  In yet another aspect, the invention comprises a method for generating a media and drug formulation according to the invention. In one embodiment, a method of producing a media according to the present invention comprises combining media components and blending such components at elevated temperatures until a single phase material is achieved. The drug formulation according to the invention is prepared by dispersing the fine drug material in the medium according to the invention in order to provide a suspension having the desired distribution of the fine drug material. In one embodiment, the method of preparing a drug formulation according to the present invention comprises a temperature at which the particulate material and the medium according to the present invention are elevated until a suspension having the desired distribution of the particulate drug material is achieved. In the process of mixing. The method of generating a media or drug formulation according to the present invention involves adding water to the components used in forming the media, the media itself, or the particulate drug material dispersed within the media. Preferably, it is implemented.

  The present invention includes media that are useful for providing non-aqueous drug formulation. The medium according to the present invention comprises at least a polymer and a solvent combined to provide a single phase material that is biocompatible, non-aqueous and miscible with water. Thus, despite being formulated from one or more polymers and one or more solvents, the polymer and the solvent used in the media according to the invention may be determined by differential scanning calorimetry (DSC). In addition, they have been selected to provide a uniform system that is both physically and chemically uniform through them. In order to achieve a biocompatible medium, the polymer and solvent used in the medium according to the present invention are selected and combined such that the resulting medium will disintegrate or degrade over time depending on the biological environment. It is done. Degradation of the medium in the biological environment can include one or more physical or chemical processes such as enzymatic action, oxidation, reduction, hydrolysis (eg, proteolysis), substitution, or solubilization, dissolution by emulsion or micelle formation. Can be generated by a dynamic process. After the media of the present invention is degraded in the biological environment, the media components are absorbed or otherwise dissipated by the body and surrounding tissue.

  The medium according to the present invention provides a medium that is miscible with water, is single phase, biocompatible, suitable for forming and maintaining a drug suspension and can provide a stable drug formulation. Thus, it may contain a pharmaceutically acceptable polymer that can be combined with a solvent. Examples of polymers useful in forming the media according to the present invention are about 0.5 to 2.0 i. v. PLA (polylactic acid) having an inherent viscosity in the range of about 0.5 to 2.0 i. v. Polyesters such as PLGA (polylactic acid polyglycolic acid) having an inherent viscosity in the range of pyrrolidone such as polyvinylpyrrolidone (having a molecular weight range of about 2,000 to 1,000,000), vinyl acetate, etc. Examples include, but are not limited to, unsaturated alcohol esters or ethers and polyoxyethylene polyoxypropylene block copolymers such as Pluronic 105. If desired, more than one different polymer or different grades of a single polymer can be used to realize the media according to the invention.

  Solvents contained within the media according to the present invention are miscible with aqueous liquids, are single phase, biocompatible, suitable for forming and maintaining drug suspensions and provide stable drug formulations. In order to provide a possible medium, it may contain a solvent that can be combined with a suitable polymer that is pharmaceutically acceptable. Although the solvent is soluble in water, such characteristics are not always required. For example, benzyl alcohol (BA) is a solvent that can be used to provide a miscible medium according to the present invention, even if BA itself is not readily soluble in water. Further examples of solvents that can be used to provide the media according to the invention are glycofurol, tetraglycol, n-methylprolidone, glycerol formal, glycerin, and propylene glycol, if desired It includes, but is not limited to, two or more solvents that can be used to provide the media according to the invention. In particular, more than one solvent may be required to provide a medium that is soluble in water and that facilitates the production of stable formulations of selected drugs.

The medium according to the present invention may be either a Newtonian fluid material or a non-Newtonian fluid material, and the viscosity of the medium varies. However, in each example, the media according to the present invention is formulated to provide a viscosity that can maintain a desired suspension of selected particulate drug material over a predetermined period of time, thereby , Can facilitate the formation of drug formulations formulated to provide controlled drug delivery at a desired rate. Accordingly, the viscosity of the media according to the present invention will vary depending on, among other things, the desired application, the size and type of particulate drug material to be included in the media, and the required media loading. The viscosity of the media according to the present invention can be varied as desired by changing the type or relative amount of solvent and polymeric material contained within the media. In one embodiment, the media of the present invention is formulated as a viscous media, the media having a viscosity in the range of about 1,000 to 10,000,000 poise. When the medium of the present invention is used as a viscous medium, the viscosity of the medium is preferably in the range of about 10,000 to 250,000 poise. Where the term viscosity is referred to herein, those viscosities were measured at 37 ° C. with a shear rate of 10 ⁻⁴ / sec using a parallel plate rheometer.

  The amount of polymer and solvent contained within the media according to the present invention may be varied to provide a media having the desired performance characteristics. In general, however, the media according to the present invention comprises from about 40% to about 80% polymer by weight and from about 20% to about 60% solvent by weight. The presently preferred embodiment of the media according to the present invention includes a media formed from a polymer and media combined in the following proportions. About 25% solvent and about 75% polymer, about 30% solvent and about 70% polymer, about 35% solvent and about 65% polymer, about 40% solvent and about 60% polymer, About 45% solvent and about 55% polymer, and about 50% solvent and about 50% polymer (all ratios given by weight). However, the media of the present invention need not be formed using only polymers and solvents.

  Apart from the polymer and the solvent, the medium according to the invention may also contain one or more surfactants or preservatives. Surfactants that can be used in the medium according to the present invention include, for example, esters such as polyhydric alcohols such as glycerol monolaurate, swells or ethers of saturated alcohols such as ethoxyl castor oil, polysorbate, myristyl lactate (Seraphil 50). ), And, for example, block copolymers of polyoxyethylene polyoxypropylene such as Pluronic, but are not limited thereto. Once the drug formulation according to the present invention has been distributed to the work environment, one or more surfactants should be included in the medium according to the present invention to facilitate the release of the drug from the medium. May be. As an alternative, one or more surfactants may be included in the medium according to the invention in order to maintain the stability of the drug to be suspended. Surfactants, when included, are typically less than about 20% by weight, but preferred surfactant ranges are less than about 10% by weight, and even about 5% by weight. Is less than. Preservatives that can be used in the media according to the present invention include, for example, antioxidants and antimicrobial agents. Examples of antioxidants that may be useful include, but are not limited to, tocopherol (vitamin E), ascorbic acid, alcorvir palmitate, butylhydroxyanisole, butylhydroxyltoluene, and propyl gallate. is not. If more than one type of preservative is incorporated into the media according to the present invention, the amount used will vary depending on the application, the preservative used, and the desired result. Generally, the preservative is included only in an amount sufficient to achieve the desired storage cure.

  The medium according to the invention is preferably produced by combining the desired components without the addition of water. In general, the media according to the present invention combine dry ingredients (eg, powdered or low moisture containing ingredients) in a dry box or under other dry conditions and raise them to an elevated temperature, Preferably it can be prepared by mixing at about 40 ° C. to about 70 ° C., allowing them to dissolve and forming a single phase. If the medium according to the present invention contains a surfactant, the solvent portion of the medium is preferably combined with the surfactant at an elevated temperature before the desired polymeric material is added for mixing. . The mixing of the components can be accomplished using any suitable equipment such as, for example, a double helix blade mixer, and the mixing step is under vacuum to remove trapped air bubbles generated from the dry components. Preferably it is completed. Once a liquid solution of the media components has been achieved, the liquid media may be removed from the mixing device to allow cooling. Differential scanning calorimetry may be used to demonstrate that the elements contained within the media have been combined to form a single phase material. The final moisture content of the medium is preferably less than 5%.

  The media of the present invention is designed to dispense drug formulation at a controlled rate over a long period of time, especially when the device is embedded or introduced into a working environment containing aqueous liquids. Facilitates the manufacture of drug formulations that act to reduce or eliminate the formation of partial or complete occlusions within the distribution channels of the device. Such performance is believed to be due at least in part to the miscibility of the medium with water, without being limited to a particular mechanism. Specifically, the miscibility of the media of the present invention with water acts to reduce or prevent phase separation of the polymer and solvent materials contained within the media when the media comes in contact with an aqueous solution. Conceivable. As a result, when the drug formulation utilizing the medium according to the present invention forms an interface with the aqueous liquid in the distribution channel of the distribution device, the polymer contained in the medium is part of the distribution channel by the polymer precipitate. Reduces the tendency to partition within an aqueous liquid in a manner that can cause manual or complete occlusion.

  The drug formulation according to the present invention includes a certain amount of drug suspended in the vehicle according to the present invention. In order to form a suspension of the drug in the medium according to the present invention, the drug is dispersed in the medium according to the present invention as a dry particulate material, which means that the drug is in a solid state (eg powder, crystal, amorphous It means to exist in the state). When forming a drug formulation according to the present invention, a medium is selected and a particulate drug material is prepared such that the drug is substantially soluble in the medium. Appropriate particulate drug and vehicle combinations can be determined by one skilled in the art based on solubility capabilities. See, for example, Giliman et al., “Pharmacological Basics of Therapeutics”, 7th Edition (1990) and Remington, “Pharmacology Science”, 18th Edition (1990).

  The amount of particulate drug material included in the drug formulation according to the invention will vary depending on, among other things, the drug's potential, the desired duration of treatment, and the desired release rate of the drug. Typically, the particulate drug material is about 0.1% to 50% by weight of the drug formulation according to the invention, with the medium comprising about 50% to about 99.9% by weight. Occupy between. In a preferred embodiment, the drug formulation according to the present invention comprises from about 1% to about 30% by weight particulate drug material.

  The drug included in the drug formulation according to the present invention can comprise any beneficial agent that exhibits the desired solubility characteristics or can be prepared as a particulate material that exhibits the desired solubility characteristics. The drug useful in the drug formulation according to the present invention can be provided in the form of a pharmacologically acceptable salt, which includes an inorganic salt, an organic salt, an inorganic group, or an organic group. Contains salt with. In one embodiment, a drug included in a drug formulation according to the present invention has a biological activity or can be used to treat a disease or other disease condition, such as a biomolecule such as a peptide or protein Material. Specific examples such as peptides or proteins that can be used in the drug formulation according to the invention include corticotropin hormones, angiotensins I and II, atrial sodium peptides, bombesin, bradykinin, calcitonin, cerebellin, dyno Rufin N, α and β endorphin, endothelin, enkephalin, epidermal growth factor, fartherin, follicular gland stimulating hormone peptide, galanin, glucagon, GLP-1, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, historelin, human growth Hormone, insulin, interferon, leuprolide, LHRH, motilin, nafarelin, neurotensin, oxytocin, ritaxin, somatostatin, substance P, tumor Examples include, but are not limited to, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, blood coagulation factor, ribozyme, and antisense oligonucleotide. Examples of peptide and protein analogs, inducers, antagonists and agents as described above can also be used. However, the drug included in the drug formulation of the present invention is not limited to the biomolecular material. The drug can provide any therapeutic or beneficial effect when administered to the work environment and can be prepared as a particulate material that exhibits the desired solubility characteristics, any pharmaceutical, vitamin, nutritional, or food product Any compound or material, including supplements, may be used.

  Any suitable particle formation process can be used to provide the particulate drug material included in the drug formulation according to the present invention. For example, methods that can be used to form particulate drug materials included in drug formulations according to the present invention include known spray drying, freeze drying, dehydration, granulation, grinding, milling, precipitation, homogenization. Or include, but are not limited to, a coating process. If the process used to form the particulate drug material produces a dry product immediately, as is the case with wet grinding or wet milling processes, the particulate drug substance is a dry product having the desired moisture content. It can be dried by any suitable method until achieved. The particulate drug material included in the drug formulation according to the present invention can be composed of a substantially pure drug or, for example, a volume replenisher, stabilizer, preservative, coating material, or desired particulate drug material. Particles comprising other antigenic reinforcing agents or excipients that provide Although not desired or required for all such materials, preparing several drug substances as particulate material containing one or more stabilizers, volume replenishers or preservatives is a degradation product. The formation of (eg, unstable intermediate chemical products) can be reduced. Antigenic reinforcements or excipients that may be useful in the formation of stabilizers, volume replenishers, preservatives and coating materials, and particulate drug materials that can be included in drug formulations according to the present invention are known in the art. Well known in the field. The type and amount of each such drug varies depending on the drug to be dispensed and the stability and solubility characteristics desired for the particulate drug material, among other factors.

  The particulate drug material included in the drug formulation according to the present invention may be used in any mixing process, blending process, or other dispersion technique that provides a drug formulation having the desired distribution of the particulate drug material. Can be dispersed in the medium according to the present invention. Preferably, the particulate drug material is dispersed in the medium using a process that does not require the addition of water. For example, combining the medium and the particulate drug material under dry conditions, and under vacuum at an elevated temperature, preferably about 40 ° C. to about 70 ° C., until the desired dispersion of the particulate drug material in the medium is achieved. By blending the materials, the particulate drug material can be dispersed in the media according to the present invention. The same equipment and techniques used to blend the media can be used to blend the particulate drug material and the media. In particular, a mixer such as, for example, a double helix blade or similar mixer can be used to blend the particulate drug material and medium to achieve drug formulation according to the present invention. After blending at an elevated temperature, the resulting drug formulation can be cooled at room temperature. After preparation, the drug formulation of the present invention may be sealed in a dry container to avoid unwanted water mixing.

The drug formulation of the present invention is stable when maintained at elevated temperatures to minimize the possibility of partial or complete blockage of the dispensing device's dispensing passage where the formulation is dispensed. Act on. In a preferred embodiment, the drug formulation of the present invention is such that at least about 80% of the drugs contained within the formulation remain chemically and physically stable after 2 months at a temperature of 40 ° C. It is prescribed as follows. In a particularly preferred embodiment, the drug formulation of the present invention is such that more than about 90% of the drugs contained within the formulation remain chemically and physically stable after 2 months at a temperature of 40 ° C. Be prescribed to be. At this time, a formulation that maintains 95% or more of the drug chemically and physically stably after 2 months at a temperature of 40 ° C. is particularly desirable. Moreover, the drug formulations according to the invention are stable when they are subjected to sterilization by radiation (eg γ-rays, β-rays or electron beams) before being exposed to elevated temperatures over a long period of time. It is preferably formulated to remain. Since they are formed using a medium according to the present invention, the drug formulation according to the present invention can be present in the distribution conduit of the dispensing device used to dispense the drug formulation. It is miscible with aqueous liquids. Such miscibility is such that the drug formulation is dispensed at a low rate (ie < 100 μl / day) and the drug formulation is dispensed over a long period of time (ie about 1 day or more). When in contact with an aqueous liquid in the conduit, it acts to reduce or eliminate the possibility of partial or complete blockage formation of the distribution conduit.

The medium and drug formulation according to the present invention can be carried in or distributed from any apparatus capable of distributing the medium or drug formulation according to the present invention at a predetermined rate over a desired period of time. can do. For example, media and drug formulations according to the present invention are described in US Pat. Nos. 3,797,492, 3,987,790, 4,008,719, 4,865,845, 5,057,318, 5,059. , 423,5,112,614,5,137,727,5,151,093,5,234,692,5,234,693,5,279,608,5,336,057,5,728,396 5,985,305, 5,997,527, 5,997,527, 5,997,902, 6,113,938, 6,132,420, 6,217,906, 6,261,584,6 , 270, 787, and 6,375, 978. However, the media and drug formulation of the present invention are not limited to application to osmotically driven pumps. For example, the media and drug formulation according to the present invention may be dispensed using a pump driven by chemical or electromechanical means. Examples of such pumps are well known in the art. Moreover, even though the media and drug formulation of the present invention are suitable for dispensing from an implantable device, the media and drug formulation can be dispensed from either an implantable device or an unimplanted device. May be.
(Example 1)
Three exemplary media according to the present invention were produced using glycofurol (GF) and polyvinylpyrrolidone (PVP). The PVP contained in each of the three media was obtained from BASF (17 pf) and had a molecular weight lower than 18,000 MW. The first medium contained 42 wt% GF and 58 wt% PVP. The second medium contained 40 wt% GF and 60 wt% PVP, and the third medium contained 50 wt% GF and 50 wt% PVP. In each example, the media was formed by first filling the raw material into a mixer. The raw material was blended at about 60 ° C. under vacuum (about −27 inches Hg) for 2 hours to achieve a single phase medium. Each of these three media is miscible with water in any proportion.
(Example 2)
The lysozyme formulation according to the present invention was produced using the second medium of Example 1 and the dried particulate lysozyme material. The lysozyme particles used in the formulation contain a ratio of 1 lysozyme to 2 sucrose and 1 methionine, and these particles are spray dried from a solution containing 25 mM citrate buffer. It was. The simulated drug formulation contained 11.2 wt% lysozyme. The lysozyme formulation was prepared by loading the appropriate amount of media and lysozyme particles in the mixer. The particles and medium were blended at about 60 ° C. under vacuum (−91.4 kPa (−27 inches Hg)) until a formulation with a substantially uniform suspension of lysozyme particles was achieved.
(Example 3)
The dispensing capacity of the lysozyme formulation of Example 2 was evaluated using two groups with six osmotic pumps. The osmotic pump was designed to dispense lysozyme formulation at 1.5 μl / day for 3 months and provide a targeted lysozyme solution rate of 35 μg / day. To evaluate the release rate performance provided by the lysozyme formulation, an osmotic pump was introduced in an aqueous medium maintained at 37 ° C. containing a phosphate buffer system (PBS).

A first group of 6 osmotic pumps was prepared using the following ingredients.
Reservoir: Titanium alloy Piston: C-Flex Lubricant: Silicone medical fluid Osmotic composition: 2 osmotic tablets (76.4% NaCl, 15.5% sodium carboxymethylcellulose, 6% povidone , 40 mg osmotic engine tablet formed using 0.5% magnesium stearate and 1.6% water) + PEG400 filler • Semipermeable membrane: injection molded into the desired plug shape Polyurethane polymer Diffusion moderator: high density polyethylene (HDPE) configured to provide a 10 mil helical distribution conduit with a diameter of 0.25 mm
Simulated drug formulation: 11.2% lysozyme particles (lysozyme: sucrose: methionine (1: 2: 1 and 25 mM citrate)) in 60% PVP and 40% GF medium
To prepare the first group of osmotic pumps, the piston and the inner diameter of the reservoir were first lightly lubricated using silicone medical fluid. The piston was inserted ˜0.5 cm into the reservoir at the membrane end of the reservoir. An amount of PEG 400 was introduced into the membrane end of the reservoir and two osmotic tablets were inserted into the same end to finish the osmotic composition. After insertion of the osmotic engine tablet, the resulting osmotic configuration was flush with the membrane edge of the reservoir. Semi-permeable membrane plugs (hereinafter simply referred to as “membrane plugs” or “plugs”) line the plug at the membrane end of the reservoir and gently push it so that the retention feature of the plug is completely within the reservoir. Until inserted into the reservoir. The lysozyme formulation is loaded into a syringe, which is injected into the reservoir by injecting the lysozyme formulation into the reservoir until the formulation is ˜3 mm from the end (at the membrane end). Used from the opposite side) to fill the reservoir. The filled reservoir was subjected to centrifugal forces (outlet end up) to remove air bubbles trapped in the lysozyme formulation during filling. The diffusion moderator was screwed into the outlet end of the reservoir until it was fully threaded. When the diffusion moderator is screwed, the excess amount of lysozyme formulation exits the distribution conduit and ensures uniform filling.

  A second group of six osmotic pumps was used to produce the first group of osmotic pumps, except that the second group of osmotic pumps utilized a diffusion moderator. Manufactured using the same components and methods. Instead of a diffusion moderator formed from HDPE plugs that form a spiral shaped distribution, the diffusion moderators included in the second group of osmotic pumps are 0.3 mm square glass capillaries glued into the HDPE plugs. Formed from. The glass capillary tube formed a substantially straight distribution conduit.

The release rate performance represented by each of the osmotic pumps comprising both the first group and the second group is shown in FIG. As shown, the three osmotic pumps from each group were “started from wet conditions”. Three osmotic pumps from each group were “started dry”. As they are used in the text, “onset of dampness” or “started from dampness” causes the osmotic pump to pump before it is introduced into the PBS medium for release rate testing. It is shown that it was injected. "Start dry" or "Start dry" indicates that the osmotic pump has not been infused before being introduced into the PBS medium for release rate testing. Infusion of the osmotic pump, starting from the wet state, was performed by simply positioning the membrane contained within the osmotic pump in PBS medium until the osmotic pump was pumped at the desired rate. After 40 days of operation in PBS medium, each of the 12 osmotic pumps is still functioning and generally dispenses an amount of lysozyme that is in the vicinity of the targeted distribution rate.
(Example 4)
Additional media according to the present invention were prepared and their miscibility characteristics were evaluated. Four different media were prepared containing benzyl alcohol (BA) as the solvent and PVP as the polymer. Two different grades of PVP from BASF (12 pf and 17 pf) were used in preparing these media. The first medium contained 40 wt% BA and 60 wt% PVP17pf. The second medium contained 38 wt% BA and 62 wt% PVP17pf. The third medium includes 26 wt% BA, 37 wt% PVP12pf, and 37 wt% PVP17pf, and the fourth media includes 27 wt% BA, 36.5 wt% PVP12pf, and It contained 36.5 wt% PVP17pf. In each example, the media was first formed by filling the raw material into a mixer. The raw material is then blended for 60 to 90 minutes at 50 ° C. under vacuum (about −28 inches Hg), resulting in a single phase medium according to the present invention. Gave rise to

Each of the four BA / PVP media prepared according to this example exhibited desirable miscibility characteristics. To assess the miscibility characteristics of these media, water or phosphate buffer solution was added to each media in various amounts, and when it was, when could phase separation be observed? It has been determined. When each of the four media was prepared, phase separation was not observed until the water or phosphate buffer content was increased to 50% or more. When phase separation was observed, each of the PVP media contained within the media was very diluted and could not condense. That is, a highly viscous polymer material could not be formed.
(Example 5)
Yet another example medium is the method described in Example 4 except that the medium was formulated using 36 wt% BA, 32 wt% PVP 12 pf, and 32 wt% PVP 17 pf. Prepared according to. The miscibility characteristics of lysozyme formulations prepared using this medium were evaluated.

  Four different litho team formulations were prepared. Each of the formulations was prepared using the media prepared in this example, as well as one of four different particulate lysozyme compositions. The particulate lysozyme composition was prepared by spray drying a lysozyme formulation prepared using citrate buffer. The particles of the first particulate lysozyme composition contained 1 to 2 sucrose in a ratio. The particles of the second particulate lysozyme composition contained a ratio of 1 lysozyme to 2 sucrose and 1 methionine. The particles of the third particulate lysozyme composition comprise a ratio of 1 lysozyme to 3 sucrose and 1 dextran, and the particles of the 4th particulate lysozyme composition comprise a ratio of 1 lysozyme to 3 sucrose and 1 Of methionine and 1 dextran. To prepare each of the four lysozyme formulations, the media prepared according to this example is combined with each of the four particulate lysozymes, in each case a substantially uniform suspension having a particle loading of 10%. A turbid liquid is achieved. Blending of the particulate lysozyme composition with the media was carried out at 60 ° C. under vacuum (about −28 inches Hg).

Once each of the four lysozyme formulations was prepared, a phosphate buffer solution was added to each, and the behavior of the four formulation phases was observed. As was true for the media prepared in Example 4, the four lysozyme formulations showed desirable miscibility characteristics. For each of the four lysozyme formulations, phase separation was not observed until the phosphate buffer content was increased to over 50%. When phase separation was observed, each of the PVP media contained within the media was very diluted and could not condense. That is, a highly viscous polymer material could not be formed.
(Example 6)
The stability of the drug as an example incorporated into the drug formulation according to the present invention was evaluated. To evaluate the stability of the drug formulation according to the present invention, two different drug formulations were prepared and stored in a titanium reservoir at a temperature of 5 ° C, 25 ° C or 40 ° C for 3 months. . After storage of the drug formulation over a three month tube, the stability of the drug contained in each formulation was determined using reverse phase, high performance liquid chromatography (RP-HPLC) and size removal chromatography (SEC). It was evaluated.

  The drug used in both drug formulations in this example was omega-interferon. Omega-interferon was prepared as a fine particle composition, which contained a ratio of 1 omega-interferon to 2 sucrose and 1 methionine. The omega-interferon particles are spray dried from a formulation containing 25 mM citrate buffer so that the formed omega-interferon particles have a ratio of 7 citrates for every 4 omega-interferon ratios. Also included. In preparing the formulation to be spray dried, a 2% solids content was targeted. When spray drying the omega-interferon particles, a pump rate of 4 ml / min was used. The inlet temperature was 120 ° C and the outlet temperature was 85 ° C.

  The media used in both drug formulations contained 40% BA and 60% PVP17pf. However, prior to blending, both BA and PVP materials were treated to remove peroxide to levels below 5 ppm. Alumina was mixed with BA for 30 minutes to remove peroxide from the BA material. The BA was then filtered through a 0.2μ filter and stored in a sealed jar under nitrogen. To remove peroxide from the PVP material, the PVP is treated with a 1% L-methionine solution and filtered therethrough using a Millipore TTF system to remove residual L-methionine and lyophilizate. It was. Peroxide levels in the treated BA and PVP materials were measured using an OXIS test kit, and the moisture level of the treated material was measured using Karl Fischer titration. Both BA and PVP materials were treated to achieve a moisture level of less than 3% and a peroxide of less than 5 ppm. After the appropriate moisture content and peroxide levels are achieved, the appropriate amount of treated BA and PVP is charged into the mixer until a single phase medium is formed (typically 60 To 90 minutes) and blended at 50 ° C. under vacuum (about −28 inches Hg). After blending, the moisture content and peroxide level of the media were confirmed to be less than 3% and less than 5 ppm, respectively.

  First and second formulations were formed using the media and omega-interferon particles described in this example. However, two drug formulations were prepared with different amounts of particulate omega-interferon. The first drug formulation (Formulation A) is prepared with a particle loading of 9.6% by weight and the second drug formulation (Formulation B) is 3.8% by weight of particles. Prepared at loading rates, the media accounted for the remainder of the formulation in each case. To prepare the drug formulation, an appropriate amount of omega-interferon particles and medium is loaded into the mixer and a vacuum (about −− until a substantially uniform suspension of omega interferon particles is achieved in the medium. 94.8 kPa (-28 inches Hg)). After the mixing step, the resulting drug formulation is placed in an oven at 50 ° C. and subjected to vacuum to remove residual air bubbles blended into the drug formulation as a result of mixing. .

  To evaluate the stability of the prepared drug formulation, the formulation was carried in a titanium reservoir lubricated with a silicone medical fluid and sealed with a fluorinated elastomer piston. Formulation A and Formulation B were carried in titanium reservoirs stored at 5 ° C, 25 ° C and 40 ° C for 3 months. After storage of an exemplary drug formulation in a titanium reservoir at specified temperature conditions, degradation of omega interferon due to oxidation and deamidation was evaluated using HPLC, and degradation of omega interferon due to aggregation was Assessed using SEC. The results of that study are shown in FIG. 2, FIG. 3 and FIG.

  FIG. 2 shows the increased omega interferon oxidation and deamidation that occurred in Formula A while storing Formula A in a titanium reservoir at the specified temperature. As can be understood with reference to FIG. 2, Formulation A provided the desired stable characteristics. In particular, even after storing Formulation A at 40 ° C. for 3 months, drug oxidation increased by about 0.25% and drug deamidation increased by less than 0.5%. It was.

  FIG. 3 shows the increased oxidation and deamidation of omega interferon that occurred in Formula B while storing Formula B in a titanium reservoir at the specified temperature. As can be understood with reference to FIG. 3, Formulation B also provided desirable stable features. In particular, even after storing Formulation B at 40 ° C. for 3 months, drug oxidation increased by about 0.25% and drug deamidation increased by about 1.3%.

  FIG. 4 shows the amount of aggregate formed in Formula A and Formula B when stored in a titanium reservoir at a specified temperature for 3 months. As can be understood with reference to FIG. 4, Formulation A and Formulation B again provided the desired stable characteristics. That is, there was no significant amount of agglomeration in any formulation even after storage at 40 ° C. for 3 months.

FIG. 1 is an osmotic pump prepared using a medium according to an embodiment of the present invention and designed to dispense lysozyme formulation at a rate of 1.5 μl / day over a period of 3 months Shows the performance of the release rate provided by the lysozyme formulation released from and shows the target lysozyme release rate of 35 μg / day. FIG. 2 shows the increased oxidation and deamidation of omega-interferon contained in a first exemplary drug formulation prepared according to the present invention (Formulation A), in 3 months. Shown after being stored at 5 ° C, 25 ° C and 40 ° C. FIG. 3 shows the increased oxidation and deamidation of omega-interferon contained in a second exemplary drug formulation (Formulation B) prepared in accordance with the present invention. Shown after being stored at 5 ° C, 25 ° C and 40 ° C. FIG. 4 shows the monomer stability of omega-interferon provided by Formula A and Formula B after the formulation has been stored at 5 ° C., 25 ° C. and 40 ° C. for 3 months. Show.

Claims (20)

A stable non-aqueous drug formulation,
At least one drug,
A non-aqueous single phase medium comprising at least one polymer and at least one solvent;
Including
The medium is miscible in water, the drug is insoluble in one or more media components, and the drug formulation is stable at 37 ° C. for at least 2 months. Simulation.   2. The stable non-aqueous drug formulation of claim 1, wherein less than about 35% of the drug is degraded by a chemical route.   6. A stable non-aqueous drug formulation according to any one of the preceding claims, wherein less than about 15% of the drug is degraded by aggregation.   The stable non-aqueous drug formulation according to any one of the preceding claims, wherein the drug comprises a particulate material.   8. A stable non-aqueous drug formulation according to any one of the preceding claims, wherein the drug comprises a pharmaceutical, vitamin, nutrient or food supplement.   6. A stable non-aqueous drug formulation according to any one of the preceding claims, wherein the drug comprises a peptide or protein.   The drugs include adrenocorticotropic hormone, angiotensin I and II, atrial sodium peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, α and β endorphin, endothelin, enkephalin, epidermal growth factor, far tirerin, follicular gland Stimulated releasing hormone peptide, galanin, glucagon, GLP-1, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, interferon, leuprolide, LHRH, motilin, nafarelin, neurotensin, oxytocin, rituxin , Somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, blood coagulation factor, ribozyi 6. A stable non-aqueous drug formulation according to any one of the preceding claims, selected from the group consisting of an active oligonucleotide and an antisense oligonucleotide.   The at least one polymer is selected from the group consisting of polyesters, pyrrolidones, esters of unsaturated alcohols, ethers of unsaturated alcohols, polyoxyethylene polyoxypropylene block copolymers, and combinations of the polymers. A stable non-aqueous drug formulation according to any one of the preceding claims.   Any of the preceding claims, wherein the at least one solvent is selected from the group consisting of glycofurol, tetraglycol, n-methylprolidone, glycerol formal, glycerin, propylene glycol, and combinations of the solvents. 2. A stable non-aqueous drug formulation according to item 1. The said medium has a viscosity in the range of about 1,000 to 250,000 poise when measured at 37 ° C with a shear rate of 10 ^-4 / sec using a parallel plate rheometer. A stable non-aqueous drug formulation according to any one of the above.   6. The stable non-restriction according to any one of the preceding claims, wherein the medium comprises from about 40 wt% to about 80 wt% polymer and from about 20 wt% to about 60 wt% solvent. Aqueous drug formulation.   A stable non-aqueous drug formulation according to any one of the preceding claims, wherein the medium exhibits a moisture content of less than 5%.   A stable non-aqueous drug formulation according to any one of the preceding claims, wherein the medium comprises glycofurol as a solvent and polyvinylpyrrolidone as a polymer.   The stable non-aqueous drug formulation according to any one of the preceding claims, wherein the medium comprises benzyl alcohol as a solvent and polyvinylpyrrolidone as a polymer. A reservoir having at least one drug dispensing orifice;
A drug dispensing device comprising: the stable non-aqueous drug formulation according to any one of claims 1 to 15.   16. A drug dispensing device according to claim 15, wherein the device is an implantable osmotic pump and the reservoir is an osmotic drug.   17. A drug dispensing device according to claim 15 or 16, wherein the device is configured to dispense the drug formulation at a rate of less than 100 microliters per day.   18. A medication dispensing device according to any one of claims 15 to 17, wherein the device is configured to dispense the medication formulation for a period longer than one day. A method for preparing a stable non-aqueous drug formulation according to any one of claims 1 to 15, comprising
Providing a non-aqueous single phase medium miscible in water comprising at least one polymer and at least one solvent;
Providing a dry particulate drug material that is insoluble in one or more components of the medium;
A method comprising mixing the drug material and the medium to form a drug formulation that is stable at 37 ° C. for at least two months.   The step of providing a dried particulate drug material comprises providing a drug material that has been subjected to spray drying, freeze drying, dehydration, granulation, grinding, milling, precipitation, homogenization, or a coating process. 19. The method according to 19.

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